Multiple myeloma (MM) is uniformly preceded by monoclonal gammopathy of undetermined significance (MGUS). While the biological significance of MGUS has been established, its clinical significance has yet to be determined. MGUS is generally discovered incidentally during the work-up of patients with signs or symptoms suggestive of MM and related malignancies. The prevalence of MGUS is high (3% and 5% of people age over 50 and 70 years, respectively), but the risk of transformation to MM and related malignancies is very low (0.4% per year after taking into account competing causes of death). Yet experts recommend indefinite annual follow- up of MGUS patients with physical examinations and laboratory tests, even though no currently available treatment can prevent malignant transformation and no evidence exists to suggest that such follow-up contributes to better clinical outcomes. In fact, follow-up may cause psychological distress to patients due to cancer anticipation, may represent an enormous economic burden on the health care system (3.6 million people in 2008 harboring MGUS), and may decrease access to cancer care (shortfall of 4000 hematologist- oncologists by 2020 projected by the American Society of Clinical Oncology). Therefore, the clinical significance of MGUS must be determined. Toward that goal, and utilizing the Surveillance Epidemiology and End Results (SEER) program and the linked Medicare data, our study has 2 specific aims. In Aim 1, we will determine whether there is a difference in overall and disease-specific survival between patients with MM and related malignancies who presented de novo and those who had a preceding diagnosis of MGUS. In Aim 2, we will compare the rates of major cancer complications (hypercalcemia, bone fracture, and dialysis- dependent kidney disease) between these 2 groups. In Aim 3, we will determine the impact of various MGUS follow-up strategies on clinical outcome. We will use the Surveillance Epidemiology and End Results (SEER) program and the linked Medicare data. PUBLIC HEALTH RELEVANCE: The findings of our study will determine whether MGUS patients who experience transformation into a malignancy and who have maintained routine follow-up have better clinical outcomes than those who have not been followed. If routine follow-up of MGUS does not result in better outcomes, discontinuing the practice has the potential to relieve the psychological distress of cancer anticipation, to considerably reduce health care cost, and to improve access to cancer care in the United States.